Diseases of iron transport and metabolism are among the most prevalent causes of human suffering and mortality. Greater than one billion people throughout the world are iron deficient and genetic variants conferring susceptibility to iron overload (hereditary hemochromatosis) are highly prevalent in some populations. As a necessary step in the development of treatments for iron deficiency and iron overload, our long-term goals are to achieve greater biochemical and structural understanding of iron transport and homeostasis. The transport of iron across membranes is substantially dependent upon protein reductases that convert or maintain iron in the correct oxidation state for transport. Ferric reductases and mechanisms of iron reduction are thus worthy of significant investigation as they may provide targets for pharmacological intervention to either promote or inhibit cellular iron uptake. We propose a combination of functional and structural studies on the Steap family of metalloreductases, which have been recently implicated in iron transport and homeostasis. These studies will provide insight into the mechanism of iron uptake in the transferrin-cycle, and appear relevant to the mechanisms of non-transferrin bound iron uptake as well. PUBLIC HEALTH RELEVANCE: The studies proposed in this grant will investigate the structural biology of iron transport and homeostasis, with an emphasis on the Steap family of metalloreductases. Defects in iron homeostasis leading to insufficient or excess iron are relevant to a slew of disease states, including cirrhosis of the liver, cancer in general and hepatocellular carcinoma in particular, diabetes, anemia and iron overload, stroke and various neurodegenerative diseases. For this reason, the Steap proteins represent potential targets of drug therapy in a variety of human disorders.